RESEARCH PROJECT 4 - ABSTRACT Alcoholic pancreatitis remains a disorder with significant morbidity and mortality, with no available treatments directed at the mechanisms of the disease. Inflammation is a major complication of pancreatitis and, to a large extent, determines its severity. There has been a significant progress in our understanding of the inflammatory response; however, this knowledge has not translated into effective therapies for pancreatitis. Thus, there is an urgent need to develop new approaches to reduce nonresolving/uncontrolled inflammation in pancreatitis, particularly in acute pancreatitis. Our recent studies reveal that impaired autophagy plays a key role in the pathogenesis of non- alcoholic and alcoholic pancreatitis. We propose to investigate the pathways linking autophagic dysfunction to inflammation in alcoholic pancreatitis. Our preliminary results suggest that impaired autophagy leads to oxidative stress (ROS increase) and accumulation of the multifunctional adaptor/scaffold protein p62/SQSTM1 in acinar cells. ROS increase and p62 accumulation, in turn, stimulate two major transcription factor pathways in exocrine pancreas, the pro-inflammatory NF-?B and the antioxidant/anti-inflammatory NRF2. Importantly, we find that NF-?B suppresses NRF2 activity, thus perpetuating the inflammatory response of alcoholic pancreatitis. These preliminary findings support our hypothesis that the interplay between NRF2 and NF-?B is a central mechanism regulating oxidative stress and inflammation in alcoholic pancreatitis; and, further, that the imbalance between excessive NF-?B and insufficient NRF2 activities drives the inflammatory response of pancreatitis. Proposed studies will determine the mechanisms regulating pancreatic NF-?B?NRF2 circuit and its role in the inflammatory response of alcoholic pancreatitis. Results from the proposed studies will identify potential molecular targets, such as NRF2, amenable for pharmacologic intervention to reduce inflammation and the severity of alcoholic pancreatitis.